Preparation method for and intermediate of pyrrolo six-membered heteroaromatic ring derivative

ABSTRACT

Disclosed are an intermediate of a pyrrolo six-membered heteroaromatic ring derivative as a JAK inhibitor and a preparation method therefor, and a method for preparing a pyrrolo six-membered heteroaromatic ring derivative using the intermediate. The method improves the reaction yield, is simple and easy to operate and control, and is conducive to expanded industrial production.

CLAIM OF PRIORITY

This application is a divisional application and claims priority to U.S.patent application Ser. No. 16/461,336, filed on May 15, 2019, which is371 U.S. National Application of PCT/CN2017/112237 filed Nov. 22, 2017,which claims priority to Chinese Application No. 201611035019.5 filedNov. 23, 2016, the entire contents of which are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pyrrolosix-membered heteroaromatic ring derivative and a pharmaceuticallyacceptable salt thereof, and an intermediate in the preparation processand a method for preparing the same. The pyrrolo six-memberedheteroaromatic ring derivative as a JAK inhibitor can be used in thepreparation of a medicament for treating myeloproliferative neoplasmsand/or leukemia.

BACKGROUND OF THE INVENTION

JAK protein kinase inhibitors, particularly JAK3 protein kinaseinhibitors, can impede activation of T-cell, and prevent graft rejectionafter transplantation. These drugs can provide a therapeutic benefit forother autoimmune diseases as well. As an important protein kinase, JAK3can also adjust the function of lymphocytes, macrophages, and mastcells. JAK3 inhibitors are expected to be involved in the treatment orprevention of a variety of diseases associated with the function oflymphocytes, macrophages, or mast cells. Some studies found that inpatients suffering from marrow fibrosis diseases, JAK2 kinase mutationwas produced in more than 50% of patients in vivo, and the increase ofthe risk of disease-related symptoms such as anemia, splenomegaly, andthe transformation to acute myeloid leukemia (AML), was closelyassociated with the increased activity due to JAK2 gene mutation andabnormal activity of JAK-STAT signaling pathway. Meanwhile, JAK2activity was increased abnormally in a variety of solid tumors andhematological tumors (glioblastoma, breast cancer, multiple myeloma,prostate cancer, AML, etc.). Therefore, the development of a selectiveinhibitor of JAK2 for myeloproliferative neoplasms and leukemia therapyhas a great medical value and market potential (a selective inhibitor ofJAK2 named Ruxolitinib (INCB-018424), developed by INCYTE Corp incooperation with NOVARTIS, has been approved by the FDA and appeared onthe market successfully).

Currently, a series of pyrrolo six-membered heteroaromatic ringderivative JAK inhibitors have been disclosed in, for example,WO2001042246, WO2002000661, WO2009054941, WO2011013785, WO2013091539A1,WO2014194741A1, etc.

Among them, WO2013091539A1 discloses a method for preparing a pyrrolosix-membered heteroaromatic ring derivative (compound 34) as follows:

There is a bare imino group present in the structure of the startingmaterial compound 1d of this method, which can react with the chlorineatom on the self six-membered ring to produce a by-product. The yield ofintermediate 5 is merely 5.0%, and the reaction time is up to 48 hours.The final product 34 is prepared from a hydrochloride of a compound offormula (III) and a compound of formula (C), and the post-treatment iscarried out by column chromatography, and the yield is merely 25.9%.This method is not conducive to industrial production. Therefore, it isnecessary to improve the existing preparation method.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is toprovide a method and an intermediate for preparing a compound of formula(IV). The yield of the intermediate is improved by changing startingmaterials, and the final product is prepared from a free base of formula(III). This method is simple and controllable, the reactants such asstarting materials are simple and easy to purchase, the reactionconditions are simple and controllable, the post-treatment process issimple, and the reaction yield is significantly improved. This method isconducive to industrial production.

The technical solution of the present invention is as follows:

The present invention provides a compound of formula (I) or astereoisomer thereof:

-   -   wherein,    -   R₁ is hydrogen or an amino protecting group;    -   R₂ is an amino protecting group;    -   R₃ is selected from the group consisting of hydrogen, C1-6 alkyl        and an amino protecting group;    -   the amino protecting group is preferably selected from the group        consisting of alkoxycarbonyl amino protecting group, acyl amino        protecting group, sulfonyl amino protecting group and alkyl        amino protecting group,    -   the alkoxycarbonyl amino protecting group is selected from the        group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl        (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl        (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl        and ethoxycarbonyl,    -   the acyl amino protecting group is selected from the group        consisting of phthalyl (Pht), trifluoroacetyl (Tfa), pivaloyl,        benzoyl, formyl and acetyl;    -   the sulfonyl amino protecting group is selected from the group        consisting of p-toluenesulfonyl (Tos or Ts),        o-nitrobenzenesulfonyl (o-Ns) and p-nitrobenzenesulfonyl (p-Ns);        and    -   the alkyl amino protecting group is selected from the group        consisting of trityl (Trt), 2,4-dimethoxybenzyl (Dmb),        p-methoxybenzyl (PMB) and benzyl (Bn).

Preferably, wherein,

-   -   R₁ is an alkoxycarbonyl amino protecting group, and the        alkoxycarbonyl amino protecting group is preferably selected        from the group consisting of benzyloxycarbonyl (Cbz),        tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and        allyloxycarbonyl (Alloc), and more preferably        tert-butoxycarbonyl (Boc);    -   R₂ is a sulfonyl amino protecting group, and the sulfonyl amino        protecting group is preferably selected from the group        consisting of p-toluenesulfonyl (Tos or Ts),        o-nitrobenzenesulfonyl (o-Ns) and p-nitrobenzenesulfonyl (p-Ns),        and more preferably p-toluenesulfonyl (Ts); and    -   R₃ is selected from the group consisting of hydrogen and methyl.

In a preferred embodiment of the present invention, the presentinvention provides a compound of formula (Ia) or a stereoisomer thereof,

In a preferred embodiment of the present invention, the presentinvention provides a compound of formula (Ib) or a stereoisomer thereof,

In a preferred embodiment of the present invention, the presentinvention provides a compound of formula (Ic) or a stereoisomer thereof,

The present invention further relates to a method for preparing thecompound of formula (I), characterized in that the method is a step ofreacting a compound of formula (A) with a compound of formula (B),

-   -   wherein,    -   X is halogen, and the halogen is selected from the group        consisting of the atoms of fluorine, chlorine, bromine and        iodine.

Preferably, the method is a reaction of a compound of formula (A) with acompound of formula (B1) to obtain a compound of formula (Ia),

Preferably, the method is a reaction of a compound of formula (A1) witha compound of formula (B1) to obtain a compound of formula (Ib),

Further preferably, the method is a reaction of a compound of formula(A2) with a compound of formula (B2) to obtain a compound of formula(Ic),

In the above schemes, the reaction is carried out in the presence of anorganic solvent and a base. After completion of the reaction, water isadded to precipitate a crystal. The mixture is filtrated, and the filtercake is dissolved in a halohydrocarbon solvent. Two phases wereseparated, and the resulting crude product is recrystallized to obtainthe product. The reaction temperature is from 30° C. to the boilingpoint of the solvent, and preferably 100° C. The organic solventincludes, but is not limited to, one or more of amide, alcohol, ether,ketone and nitrile, preferably N,N-dimethylacetamide,N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, methanol,ethanol, dimethyl sulfoxide and 1,4-dioxane, and more preferablyN,N-dimethylformamide (DMF). The base includes, but is not limited to,an organic base and an inorganic base. The organic base includes, but isnot limited to, triethylamine, N,N-diisopropylethylamine,n-butyllithium, potassium tert-butoxide, sodium tert-butoxide,1,8-diazabicycloundec-7-ene, pyridine and 4-dimethylaminopyridine. Theinorganic base includes, but is not limited to, sodium hydride, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassium phosphate,lithium carbonate, lithium hydrogen phosphate, potassium bicarbonate andcesium carbonate, and preferably potassium carbonate. Thehalohydrocarbon solvent is preferably dichloromethane. Therecrystallization method can be carried out by a conventionalrecrystallization process. For example, the starting compound can bedissolved in an organic solvent by heating, then cooled slowly toprecipitate a crystal, and the mixture is filtrated after the completionof crystallization and dried to obtain the desired crystal.Alternatively, the target product can be obtained by a goodsolvent/anti-solvent recrystallization method (good solvent/anti-solventmethod).

The present invention also relates to a compound of formula (I′) or astereoisomer thereof:

-   -   wherein, R₂ and R₃ are as defined in formula (I).

Preferably, the present invention provides a compound of formula (I′-1)or a stereoisomer thereof,

Further preferably, the present invention provides a method forpreparing a compound of formula (IV), characterized in that the methodcomprises a step of obtaining the compound of formula (IV) from acompound of formula (I′) by an one-step reaction or multi-step reaction,

More preferably, the present invention provides a method for preparingthe compound of formula (IV), characterized in that the method consistsin obtaining the compound of formula (IV) from a compound of formula(I′-1) by an one-step reaction or multi-step reaction,

Preferably, the compound of formula (I′-1) and phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate are subjected to asubstitution reaction to obtain the compound of formula (IV).

Further preferably, the compound of formula (I′-1) and phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate are reacted in an organicsolvent, and then a crystal is precipitated, filtrated and dried toobtain the target compound of formula (IV).

The present invention also relates to a method for preparing thecompound of formula (IV), characterized in that the method comprises astep of obtaining the compound of formula (IV) from a compound offormula (Ic) by an one-step reaction or multi-step reaction,

Preferably, the compound of formula (Ic) and phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate are subjected to asubstitution reaction to obtain the compound of formula (IV).

Further preferably, the compound of formula (Ic), phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate and a base are reacted in anorganic solvent, and then a crystal is precipitated, filtrated and driedto obtain the target compound of formula (IV).

In the above schemes, the organic solvent includes, but is not limitedto, one or more of amide, alcohol, ether, ester, halohydrocarbon,aliphatic hydrocarbon, ketone and nitrile, preferably n-butane,n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran,dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile,methanol, ethanol, toluene, dimethyl sulfoxide, 1,4-dioxane and methylether, and more preferably tetrahydrofuran. The base includes, but isnot limited to, an organic base and an inorganic base. The organic baseincludes, but is not limited to, triethylamine,N,N-diisopropylethylamine, n-butyllithium, potassium tert-butoxide,sodium tert-butoxide, 1,8-diazabicycloundec-7-ene, pyridine and4-dimethylaminopyridine. The inorganic base includes, but is not limitedto, sodium hydride, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium phosphate, lithium carbonate, lithium hydrogenphosphate, potassium bicarbonate and cesium carbonate. The base ispreferably triethylamine. The reaction temperature is from 15° C. to theboiling point of the solvent, and preferably from 50° C. to the boilingpoint of the solvent.

The present invention also relates to a method for preparing thecompound of formula (IV), characterized in that the method comprises astep of reacting a compound of formula (III) with a compound of formula(C) to obtain the compound of formula (IV),

Preferably, the free base compound of formula (III) and phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate are subjected to asubstitution reaction to obtain the compound of formula (IV).

Further preferably, the free base compound of formula (III), phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate and a base are reacted in anorganic solvent, and then a crystal is precipitated, filtrated and driedto obtain the target compound of formula (IV).

More preferably, the organic solvent includes, but is not limited to,one or more of amide, alcohol, ether, ester, halohydrocarbon, aliphatichydrocarbon, ketone and nitrile, preferably n-butane, n-hexane,N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran,dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile,methanol, ethanol, toluene, dimethyl sulfoxide, 1,4-dioxane and methylether, and more preferably tetrahydrofuran. The base includes, but isnot limited to, an organic base and an inorganic base. The organic baseincludes, but is not limited to, triethylamine,N,N-diisopropylethylamine, n-butyllithium, potassium tert-butoxide,sodium tert-butoxide, 1,8-diazabicycloundec-7-ene, pyridine and4-dimethylaminopyridine. The inorganic base includes, but is not limitedto, sodium hydride, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium phosphate, lithium carbonate, lithium hydrogenphosphate, potassium bicarbonate and cesium carbonate. The base ispreferably triethylamine. The reaction temperature is from 15° C. to theboiling point of the solvent, and preferably from 50° C. to the boilingpoint of the solvent. The present invention further relates to a methodfor preparing the compound of formula (III), characterized by removingthe amino protecting groups of a compound of formula (Ia) to obtain thecompound of formula (III),

-   -   wherein R₁ and R₂ are as defined in formula (I).

Preferably, the deprotection reaction of the above scheme is a two-stepdeprotection reaction.

More preferably, the deprotection reaction of the above scheme is anone-step deprotection reaction.

In the above scheme, the two-step amino deprotection reaction comprisesthe steps of,

-   -   step 1, removing an amino protecting group of the intermediate        compound of formula (Ia) to obtain an intermediate compound of        formula (II);    -   step 2, removing an amino protecting group of the intermediate        compound of formula (II) to obtain the compound of formula        (III).

Preferably, the method for preparing the compound of formula (III) ischaracterized by obtaining the compound of formula (III) from a compoundof formula (Ib) by a two-step amino deprotection reaction,

Further preferably, the method for preparing the compound of formula(III) is characterized by obtaining the compound of formula (III) from acompound of formula (Ic) by a two-step amino deprotection reaction,

More preferably,

The intermediate of formula (Ia) in step 1 is reacted with a base in anorganic solvent under heating to remove an amino protecting group. Thereaction solution is extracted, and the resulting crude product ispulped in a mixed solvent of an ester and an ether to obtain the targetintermediate of formula (II). The heating temperature is from 50° C. tothe boiling point of the solvent, and preferably 70° C. The organicsolvent includes, but is not limited to, one or more of amide, alcohol,ether, ketone and nitrile, preferably N,N-dimethylacetamide,N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile andmethanol, and more preferably N,N-dimethylacetamide. The base includes,but is not limited to, an organic base and an inorganic base. Theorganic base includes, but is not limited to, lithium diisopropylamide(LDA), n-butyllithium, sodium ethoxide, sodium methoxide, sodiumethoxide, potassium ethoxide and sodium tert-butoxide. The inorganicbase includes, but is not limited to, sodium hydroxide, potassiumhydroxide, sodium ethoxide, sodium methoxide, sodium ethoxide, potassiumethoxide, sodium tert-butoxide, sodium hydroxide and potassiumhydroxide, and preferably sodium hydroxide and potassium hydroxide.

More preferably,

The intermediate of formula (II) in step 2 is reacted with an acid in anorganic solvent to remove an amino protecting group. The extracted waterphase is added with a base to adjust the pH and precipitate a solid. Thesolid is filtrated, pulped, filtrated again and dried to obtain thetarget intermediate of formula (III). The organic solvent includes, butis not limited to, an alcohol, ketone, nitrile, a mixed solvent of analcohol and a halohydrocarbon, a mixed solvent of an alcohol and anether, a mixed solvent of an alcohol and an ester, a mixed solvent of aketone and a halohydrocarbon, a mixed solvent of a ketone and an ether,a mixed solvent of a ketone and an ester, a mixed solvent of a nitrileand a halohydrocarbon, a mixed solvent of a nitrile and an ether, and amixed solvent of a nitrile and an ester, preferably methanol, ethanol,acetone, acetonitrile, methanol/dichloromethane, methanol/ethyl acetate,methanol/1,4-dioxane, acetone/dichloromethane, acetone/ethyl acetate,acetone/1,4-dioxane, acetonitrile/dichloromethane, acetonitrile/ethylacetate and acetonitrile/1,4-dioxane, and more preferablymethanol/dichloromethane. The acid is selected from the group consistingof formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonicacid, isethionic acid, hydrochloric acid and trifluoroacetic acid, andpreferably hydrochloric acid. The base is selected from metal hydroxide,preferably sodium hydroxide or potassium hydroxide.

Most preferably, wherein,

R₁ is an alkoxycarbonyl amino protecting group, and the alkoxycarbonylamino protecting group is preferably selected from the group consistingof benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc),fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc), and morepreferably tert-butoxycarbonyl (Boc);

-   -   R2 is a sulfonyl amino protecting group, and the sulfonyl amino        protecting group is preferably selected from the group        consisting of p-toluenesulfonyl (Tos or Ts),        o-nitrobenzenesulfonyl (o-Ns) and p-nitrobenzenesulfonyl (p-Ns),        and more preferably p-toluenesulfonyl (Ts).

In the above scheme, the one-step amino deprotection reaction comprisesa step of simultaneously removing the two amino protecting groups of thecompound of formula (Ia) by an one-step reaction to obtain the compoundof formula (III),

Preferably, the two amino protecting groups of the compound of formula(Ib) are simultaneously removed by an one-step reaction to obtain thecompound of formula (III),

Preferably, the two amino protecting groups of the compound of formula(Ic) are simultaneously removed by an one-step reaction to obtain thecompound of formula (III),

Further preferably, wherein,

-   -   R₁ is an alkoxycarbonyl amino protecting group, and the        alkoxycarbonyl amino protecting group is preferably selected        from the group consisting of benzyloxycarbonyl (Cbz),        tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and        allyloxycarbonyl (Alloc), and more preferably        tert-butoxycarbonyl (Boc);    -   R₂ is a sulfonyl amino protecting group, and the sulfonyl amino        protecting group is preferably selected from the group        consisting of p-toluenesulfonyl (Tos or Ts),        o-nitrobenzenesulfonyl (o-Ns) and p-nitrobenzenesulfonyl (p-Ns),        and more preferably p-toluenesulfonyl (Ts).

In one aspect, the present invention relates to a method for preparingthe compound of formula (IV), characterized in that the method comprisesthe following steps of,

Step 1, Preparation of intermediate Ic

Compounds A2 and B2 are dissolved in an organic solvent under theprotection of inert gas, and heated to react after adding a base. Aftercompletion of the reaction, the reaction solution is cooled to roomtemperature, added with water and filtrated. The solid is dissolved in ahalohydrocarbon solvent, and then extracted. The solution is dried, andthen concentrated under reduced pressure to obtain the intermediate Ic.The organic solvent includes, but is not limited to, one or more ofamide, alcohol, ether, ketone and nitrile, preferably n-butane,n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran,acetone, acetonitrile, methanol, ethanol, dimethyl sulfoxide and1,4-dioxane, and more preferably N,N-dimethylformamide. The baseincludes, but is not limited to, an organic base and an inorganic base.The organic base includes, but is not limited to, triethylamine,N,N-diisopropylethylamine, n-butyllithium, potassium tert-butoxide,sodium tert-butoxide, 1,8-diazabicycloundec-7-ene, pyridine and4-dimethylaminopyridine. The inorganic base includes, but is not limitedto, sodium hydride, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium phosphate, lithium carbonate, lithium hydrogenphosphate, potassium bicarbonate and cesium carbonate, and preferablypotassium carbonate. The halohydrocarbon solvent is preferablydichloromethane.

Step 2, Preparation of intermediate IIa

The intermediate Ic is dissolved in an organic solvent, added with abase and water under stirring, and heated to react. After completion ofthe reaction, the reaction solution is cooled to room temperature, addedwith water and a halohydrocarbon solvent, and extracted. The reactionsolution is dried, and concentrated under reduced pressure to obtain theintermediate IIa. The organic solvent includes, but is not limited to,one or more of amide, alcohol, ether, ketone and nitrile, preferablyN,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, acetone,acetonitrile and methanol, and more preferably N,N-dimethylacetamide.The base includes, but is not limited to, an organic base and aninorganic base. The organic base includes, but is not limited to,lithium diisopropylamide (LDA), n-butyllithium, sodium ethoxide, sodiummethoxide, sodium ethoxide, potassium ethoxide and sodium tert-butoxide.The inorganic base includes, but is not limited to, sodium hydroxide andpotassium hydroxide, and preferably sodium hydroxide or potassiumhydroxide. The halohydrocarbon solvent is preferably dichloromethane.

Step 3, Preparation of intermediate III

The intermediate IIa is dissolved in an organic solvent, added dropwisewith an acid at low temperature, and stirred to react at roomtemperature. After completion of the reaction, the reaction solution isconcentrated, added with water to dissolve, and added with ahalohydrocarbon solvent to extract. The water phase is added with a baseto adjust the pH to alkaline and precipitate a solid. The solid isfiltrated and dried to obtain the intermediate III.

The organic solvent includes, but is not limited to, an alcohol, ketone,nitrile, a mixed solvent of an alcohol and a halohydrocarbon, a mixedsolvent of an alcohol and an ether, a mixed solvent of an alcohol and anester, a mixed solvent of a ketone and a halohydrocarbon, a mixedsolvent of a ketone and an ether, a mixed solvent of a ketone and anester, a mixed solvent of a nitrile and a halohydrocarbon, a mixedsolvent of a nitrile and an ether, and a mixed solvent of a nitrile andan ester, preferably methanol, ethanol, acetone, acetonitrile,methanol/dichloromethane, methanol/ethyl acetate, methanol/1,4-dioxane,acetone/dichloromethane, acetone/ethyl acetate, acetone/1,4-dioxane,acetonitrile/dichloromethane, acetonitrile/ethyl acetate andacetonitrile/1,4-dioxane, and more preferably methanol/dichloromethane.The acid is selected from the group consisting of formic acid, aceticacid, methanesulfonic acid, p-toluenesulfonic acid, isethionic acid,hydrochloric acid and trifluoroacetic acid, and preferably hydrochloricacid. The base is preferably an inorganic base, and the inorganic baseis preferably a metal hydroxide, such as sodium hydroxide and potassiumhydroxide. The pH to alkaline is preferably from 8 to 11, and morepreferably from 9 to 10.

Step 4, Preparation of product IV

The intermediate III and compound C are added to an organic solvent,added with a base, and heated to react. After completion of thereaction, the reaction solution is cooled to precipitate a crystal,which is then filtrated and dried to obtain the product IV. The organicsolvent includes, but is not limited to, an amide, alcohol, ether,ester, halohydrocarbon, aliphatic hydrocarbon, ketone and nitrile,preferably n-butane, n-hexane, N,N-dimethylacetamide,N,N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform,ethyl acetate, acetone, acetonitrile, methanol, ethanol, toluene,dimethyl sulfoxide, 1,4-dioxane and methyl ether, and more preferablytetrahydrofuran. The base includes, but is not limited to, an organicbase and an inorganic base. The organic base includes, but is notlimited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium,potassium tert-butoxide, sodium tert-butoxide,1,8-diazabicycloundec-7-ene, pyridine and 4-dimethylaminopyridine. Theinorganic base includes, but is not limited to, sodium hydride, sodiumcarbonate,

-   -   potassium carbonate, sodium bicarbonate, potassium phosphate,        lithium carbonate, lithium hydrogen phosphate, potassium        bicarbonate and cesium carbonate. The base is preferably        triethylamine.

In another aspect, the present invention relates to a method forpreparing a pharmaceutically acceptable salt of the compound of formula(IV), comprising the steps in the above schemes, and a step of reactingthe compound of formula (IV) with an acid to obtain a pharmaceuticallyacceptable salt thereof, wherein the acid is selected from the groupconsisting of an organic acid and an inorganic acid, and preferably aninorganic acid; the organic acid is selected from the group consistingof citric acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaricacid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonicacid and methanesulfonic acid; the inorganic acid is selected from thegroup consisting of hydrochloric acid, sulfuric acid and phosphoricacid, and preferably sulfuric acid.

DETAILED DESCRIPTION OF THE INVENTION

In the specification and claims of the present application, unlessotherwise indicated the scientific and technical terms used herein havethe meanings generally understood by a person skilled in the art.However, in order to understand the present invention better,definitions and explanations of some related terms are provided. Inaddition, when the definitions and explanations of the terms provided inthe present application are inconsistent with the meanings generallyunderstood by a person skilled in the art, the definitions andexplanations of the terms provided in the present application shallprevail.

The term “protecting group” used in the present invention means thatwhen a multifunctional organic compound is subjected to a reaction, inorder to make the reaction occur only at a desired group and to preventother groups from being affected, other groups are protected before thereaction and recovered after the reaction is completed. A reagent thatprotects a certain group is called a protecting group for the group. Thebasic principles for choosing a protecting group are as follows: theprotection reaction and deprotection reaction are required to be mildand easy to operate, the reaction has a high yield and less sidereactions, the product is easy to purify, and the reagents does notinvolve in other reactions and are cheap and easy to purchase, etc.

The term “amino protecting group” used in the present invention refersto a group capable of protecting an amino group from reactions.Conventional amino protecting groups include, but are not limited to:formate (prepared by the reaction of an amino group with chloroformate,diazocarboxylate or various carbonates), imine (prepared by the reactionof a primary amine with aromatic aldehyde, aromatic ketone or fattyketone), alkoxycarbonyl (benzyloxycarbonyl (Cbz), tert-butoxycarbonyl(Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc),trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl andethoxycarbonyl), acyl (prepared by the reaction of an amino group withacid chloride or anhydride, for example phthalyl (Pht), trifluoroacetyl(Tfa), pivaloyl, benzoyl, formyl and acetyl), sulfonyl (aromaticsulfonamide such as p-toluenesulfonyl (Tos or Ts),o-nitrobenzenesulfonyl (o-Ns) and p-nitrobenzenesulfonyl (p-Ns)), alkyl(trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) andbenzyl (Bn)) and the like, wherein “alkoxycarbonyl, acyl and sulfonyl”refer to R—O—C(O)—, R—C(O)— and R—S(O)2-, respectively, wherein R can behydrogen, alkyl or aryl.

The term “pulping” used in the present invention refers to apurification method utilizing the property that the solubility of acompound is poor in a solvent, while the solubility of impurities isgood in the solvent. Pulping purification can remove color, changecrystal form or remove small amounts of impurities.

The term “halogenated” used in the present invention refers to besubstituted by a “halogen atom”. The term “halogen atom” refers tofluorine, chlorine, bromine and iodine.

The term “C1-6 alkyl” used in the present invention refers to a straightor branched alkyl containing 1 to 6 carbon atoms, including for example“C1-4 alkyl”, “C1-3 alkyl” and the like. Its specific examples include,but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl,neo-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

The term “cyano” used in the present invention refers to a —CN group.

The term “amide organic solvent” used in the present invention refers toa liquid compound in which a hydroxy group in a carboxyl group of acarboxylic acid molecule is substituted with an amino or a hydrocarbonamino group (—NHR or —NR2). It can also be regarded as a liquid compoundin which a hydrogen on a nitrogen atom of an ammonia or amine moleculeis substituted with an acyl. Its specific examples include, but are notlimited to: N,N-dimethylformamide or N,N-dimethylacetamide.

The term “ether solvent” used in the present invention refers to a chaincompound or a cyclic compound having an ether bond —O— and having 1 to10 carbon atoms. Its specific examples include, but are not limited to:propylene glycol methyl ether, tetrahydrofuran or 1,4-dioxane.

The term “ester solvent” used in the present invention refers to acombination of a lower organic acid having 1 to 4 carbon atoms and alower alcohol having 1 to 6 carbon atoms. Its specific examples include,but are not limited to: ethyl acetate, isopropyl acetate or butylacetate.

The term “alcohol solvent” used in the present invention refers to agroup derived from the substitution of one or more hydrogen atom(s) onthe “C1-6 alkyl” with one or more “hydroxy(s)”, wherein the “hydroxy”and “C1-6 alkyl” are as defined above. Its specific examples include,but are not limited to: methanol, ethanol, n-propanol or 2-propanol.

The term “halohydrocarbon solvent” used in the present invention refersto a group derived from the substitution of one or more hydrogen atom(s)on the “C1-6 alkyl” with one or more “halogen atom(s)”, wherein the“halogen atom” and “C1-6 alkyl” are as defined above. Its specificexamples include, but are not limited to: chloromethane,dichloromethane, chloroform or carbon tetrachloride.

The term “ketone solvent” used in the present invention refers to acompound in which a carbonyl group (—C(O)—) is bonded to two hydrocarbongroups. Ketones can be classified into aliphatic ketones, alicyclicketones, aromatic ketones, saturated ketones, and unsaturated ketones,depending on the hydrocarbon groups in the molecule. Its specificexamples include, but are not limited to: acetone, methyl butanone ormethyl isobutyl ketone.

The term “nitrile solvent” used in the present invention refers to agroup derived from the substitution of one or more hydrogen atom(s) onthe “C1-6 alkyl” with one or more “cyano(s)”, wherein the “cyano” and“C1-6 alkyl” are as defined above. Its specific examples include, butare not limited to: acetonitrile or propionitrile.

The term “aliphatic hydrocarbon solvent” used in the present inventionrefers to a hydrocarbon having the basic properties of an aliphaticcompound and having 1 to 10 carbon atoms, wherein the carbon atoms inthe molecule are linked to a chain-like carbon frame in which the twoends are opened and do not form a ring, for example saturated aliphatichydrocarbon, including alkane solvent. Its specific examples include,but are not limited to: n-butane, n-pentane, n-hexane or n-heptane.“Substituted” means that one or more hydrogen atoms in a group,preferably up to 5, and more preferably 1 to 3 hydrogen atoms, are eachindependently substituted by a corresponding number of substituents. Itgoes without saying that the substituents only exist in their possiblechemical position. The person skilled in the art is able to determinewhether the substitution is possible or impossible by experiments ortheory without paying excessive efforts. For example, the combination ofamino or hydroxy having a free hydrogen and carbon atoms havingunsaturated (e.g., olefinic) bonds may be unstable.

The term “mixed solvent” used in the present invention refers to asolvent obtained by mixing one or more different kinds of organicsolvents in a certain ratio, or a solvent obtained by mixing an organicsolvent and water in a certain ratio. The mixed solvent is preferably amixed solvent of an alcohol and a halohydrocarbon or a mixed solvent ofan ester and an ether. The mixed solvent of an alcohol and ahalohydrocarbon is preferably a mixed solvent of methanol anddichloromethane, the certain ratio may be volume ratio or mass ratio,the mass ratio is from 10:1 to 1:10, and preferably 1.6:1. The mixedsolvent of an ester and an ether is preferably a mixed solvent of ethylacetate and petroleum ether, the certain ratio may be volume ratio ormass ratio, the volume ratio is from 1:1 to 1:10, and preferably 1:4.

The term “acid” used in the present invention refers to an organic acidor an inorganic acid. “Organic acid” refers to a compound capable ofaccepting an electron pair according to the general theory of acid-base.The organic acid includes carboxylic acid, halogenated acid, hydroxyacid, keto acid, amino acid, sulfonic acid, sulfinic acid, sulfuricacid, phenolic acid and the like, and preferably sulfonic acid. Thespecific examples of sulfonic acid include, but are not limited to:formic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid,dodecylbenzenesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, trifluoromethanesulfonic acid, trifluoroacetic acid, isethionicacid and the like. “Inorganic acid” refers to an inorganic compoundcapable of dissociating a hydrogen ion. According to the composition,the inorganic acids can be classified into oxyacids, hydrogen acids,complex acids, mixed acids, super acids and the like, and the inorganicacid is preferably an oxyacid or hydrogen acid. The specific examples ofoxyacid include, but are not limited to: carbonic acid, nitric acid,nitrous acid, hypochlorous acid, sulfuric acid, phosphoric acid and thelike. The specific examples of hydrogen acid include, but are notlimited to: hydrofluoric acid, hydrochloric acid, bromic acid, hydrogensulfide and the like.

The term “base” used in the present invention refers to an organic baseor an inorganic base. “Organic base” refers to a compound capable ofgiving an electron pair according to the general theory of acid-base.The organic bases are classified into amines, amides, alkali metal saltsof an alcohol, alkyl lithium compounds, lithium amide compounds,nitrogen-containing heterocyclic compounds, organic bases providing ahydroxide, amino acids and the like. Its specific examples include, butare not limited to: dimethylamine, triethylamine, ethylenediamine,colchicine, sodium methoxide, sodium ethoxide, potassium ethoxide,sodium tert-butoxide, lithium tert-butoxide, n-butyl lithium,N,N-diisopropylethylamine, lithium diisopropylamide (LDA), pyrrolidine,pyridine, tetramethylammonium hydroxide, 1,8-diazabicycloundec-7-ene,4-dimethylaminopyridine, lysine (Lys) and the like. “Inorganic base”refers to an inorganic compound capable of dissociating a hydroxide ion.According to the composition, the inorganic bases can be classified intometallides, metal hydroxides, ammonia or ammonia monohydrate, saltscapable of dissociating a hydroxide ion and the like. Its specificexamples include, but are not limited to: sodium hydride, lithiumhydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide,magnesium hydroxide, sodium carbonate (soda ash), potassium carbonate,sodium bicarbonate (baking soda), potassium phosphate, lithiumcarbonate, lithium hydrogen phosphate, potassium bicarbonate, cesiumcarbonate and the like. Triethylamine, N,N-diisopropylethylamine,n-butyl lithium, potassium tert-butoxide, sodium tert-butoxide. Theinorganic bases include, but are not limited to sodium hydride, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate and cesium carbonate.

The term “pharmaceutically acceptable salt or medicinal salt” used inthe present invention refers to a salt of the compound of the presentinvention, which is safe and effective in mammals and has the desiredbiological activity. The salt is specifically a compound formed by thecompound of the present invention with an inorganic or organic acid. Itsspecific examples include, but are not limited to: citrate,hydrochloride, sulfate, hydrosulphate, phosphate, acetate,trifluoroacetate, oxalate, tartrate, maleate, fumarate, sulfonate,p-toluenesulfonate, benzenesulfonate, ethanesulfonate andmethanesulfonate.

Advantageous effects of the present invention

Compared with the prior art (WO2013091539A1, publication date: 27 Jun.2013), the technical solution for preparing the compound of formula (IV)of the present invention has the following advantages:

(1) The present invention is different from the prior art in startingmaterial. The nitrogen atom on the pyrrolyl group of the startingmaterial the compound of formula of the present invention is protectedby a protecting group before reacting with the compound of formula (B),which can avoid the reaction between the bare amino on the five-memberedring of the compound of formula (A) and the halogen on the selfsix-membered ring, that is to say, thereby reducing side reactions thatwill cause the incomplete reaction between the compound of formula (A)and the compound of formula (B) and cause the decrease in product yieldand increase in impurities.

(2) The prior art discloses a method for preparing the target productfrom a salt of the compound of formula (III), wherein triethylamine isfirstly reacted with the hydrochloride salt of

-   -   the compound of formula (III) (above) to dissociate the compound        of formula (III), which is then reacted with the compound of        formula (C) to obtain the target product. However, this method        may leave too much compound of formula (III), and the reaction        is incomplete. In the present invention, the protecting group of        the compound of formula (I) is removed to obtain the free        compound of

-   -   formula (III) (above), which is then reacted with the compound        of formula (C) to obtain the target final product. The method of        the present invention is easy to operate, and can improve the        yield and purity of the product. Moreover, during the        preparation of the compound of formula (III) in this method, the        process of pH adjustment by adding a base can also remove the        impurities, thus the resulting compound of formula (III) has a        high purity.

The reaction time is shortened. The reaction time of the first step forpreparing the compound of formula (IIa) of the present invention is 2hours, and the reaction time of the second step is 1 hour, while thereaction time of the first step disclosed in the prior art is 48 hours.

(4) The yield is improved. The yield of the first step of the presentinvention is 60-70%, the yield of the second step is 80-90%, and thetotal yield of the two steps is 48-63%, while the yield of the prior artis 5.0%; the yield of the final step of the present invention is 80-90%,while that of the prior art is 25.9%.

(5) The post-treatment process is simple. The post-treatment process ofthe present invention is cooling to precipitate a crystal, and simplywashing to remove the impurities, thereby obtaining the target product,while that of the prior art is column chromatography separation andpurification. The post-treatment process of the present invention isconducive to industrial production.

Preferred Embodiments

The present invention will be further described with reference to thefollowing examples. The examples of the present invention are only usedto illustrate the technical solutions of the present invention, andshould not be considered as limiting the spirit and scope of the presentinvention.

In the examples of the present invention, the experiment methods that donot specify the specific conditions are generally conducted inaccordance with conventional conditions, or in accordance withconditions recommended by the material or product manufacturers. Thereagents without specific source are commercially available conventionalreagents.

EXAMPLES

The structures of the compounds were identified by nuclear magneticresonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) were givenin 10-6 (ppm). NMR was determined by a Bruker AVANCE-400 machine. Thesolvents for determination were deuterated-dimethyl sulfoxide (DMSO-d6)and deuterated-chloroform (CDCl3), and the internal standard wastetramethylsilane (TMS).

MS was determined by a FINNIGAN LCQAd (ESI) mass spectrometer(manufacturer: Thermo, type: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) was determined on anAgilent high pressure liquid chromatograph and a Thermon UltiMate3000high performance liquid chromatograph (Kromasil C18 250×4.6 mm column).

Preparation Example 1. The method for preparing the starting materialthe compound of formula (A2) is as follows:

Preparation of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 kg, 12.96 mol) anddichloromethane (40 L) were added to a reaction flask at roomtemperature, and stirred to dissolve. Triethylamine (3.88 kg, 38.4 mol)and 4-dimethylaminopyridine (157.6 g, 1.28 mol) were added successively,and stirred to dissolve. A solution of p-toluenesulfonyl chloride (2.6kg, 13.6 mol) in dichloromethane (30 L) was added dropwise at 0° C.,followed by stirring at room temperature for 30 minutes. After TLCshowed that the reaction was completed, the reaction solution was washedwith water (16 L×3). The organic phases were combined, dried overanhydrous sodium sulfate and filtrated. The filtrate was concentratedand dried under reduced pressure to obtain the title product (3.9 kg,yield 97.7%).

MS m/z (ESI): 309.0 [M+1]

¹H-NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.10-8.08 (d, 2H), 7.79-7.78(d,1H), 7.34-7.32 (d, 2H), 6.72-6.71 (d, 1H), 2.41(s, 3H).

Preparation Example 2. The starting material the compound of formula(B2) was prepared by the known methods disclosed in the Example 1 ofWO2008089636A1 (publication date 31 Jul. 2008) and the Example 5 ofWO2013091539A1 (publication date 27 Jun. 2013).

MS m/z (ESI): 241.5 [M+1]

¹H-NMR (400 MHz, CDCl₃) δ 3.21 (m, 2H), 2.90-2.83 (m, 3H), 2.47-2.45 (m,2H), 2.08 (s, 3H), 1.42-1.33 (m, 4H), 1.15 (s, 9H), 0.94 (s, 1H).

Preparation Example 3. The method for preparing the starting materialthe compound of formula (C) is as follows:

(1) Preparation of 1-(isothiocyanatomethyl)-4-methoxybenzene

Methoxybenzylamine (14 kg), tetrahydrofuran (50 L) and triethylamine(26.8 kg) were added to a reactor, and stirred to dissolve. A solutionof carbon disulfide (7.8 kg) in tetrahydrofuran (5 L) was added dropwiseat 10-15° C. After completion of the dropwise addition, a solid wasprecipitated from the reaction solution, and the reaction was stirred at10-20° C. for 30 minutes. A solution of p-toluenesulfonyl chloride (20.5kg) in tetrahydrofuran (50 L) was added dropwise at 10-20° C. Aftercompletion of the dropwise addition, the reaction was stirred for 30minutes. After TLC showed that the reaction was completed, the reactionsolution was added with petroleum ether (30 L) and purified water (100L) to extract, and two phases were separated. The organic phase waswashed with dilute hydrochloric acid (40 L) until pH=4-5, and thenwashed with water (40 L) and brine (25 L) successively. Two phases wereseparated, the organic phase was dried over anhydrous sodium sulfate,filtrated and concentrated under reduced pressure to obtain the titleproduct (21.2 kg, yield 116%).

(2) Preparation of3-methoxy-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine

DMF (40 L), O-methylisourea sulfate (7.5 kg) and sodium bicarbonate (6kg) were added to a reactor, and the reaction was stirred at 30-40° C.for 0.5 hour. A solution of 1-(isothiocyanatomethyl)-4-methoxybenzene(21.2 kg) in N,N-dimethylformamide (5 L) was added, and the reaction wasstirred at 30-40° C. for 6-8 hours. After TLC showed that the reactionwas completed, diisopropyl azodicarboxylate (12.9 kg) was added dropwiseat 30-40° C. After completion of the dropwise addition, the reaction wasstirred at 35-45° C. for 2 hours. After TLC showed that the reaction wascompleted, the reaction solution was added with purified water (180 L)and stirred for 2-3 hours, and a large amount of light yellow solidswere precipitated. The reaction mixture was filtrated by centrifugation,and spin-dried. The filter cake was washed with water and petroleumether successively, filtrated and dried to obtain the title product(278.7 g, yield 110%).

(3) Preparation of 3-methoxy-1,2,4-thiadiazol-5-amine

3-Methoxy-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (12.4 kg) andtrifluoroacetic acid (25 L) were added to a reaction flask under anargon atmosphere, and the reaction was stirred at 73-75° C. for 7-9hours. After TLC showed that the reaction was completed, the reactionsolution was concentrated under reduced pressure to obtain a brownliquid. The liquid was cooled to room temperature, and added withhydrochloric acid (1N, 5 L) and petroleum ether:ethyl acetate (5 L,V/V=1:1) under stirring. After stirring to dissolve, the reactionsolution was filtrated, and the filter cake was washed with 1Nhydrochloric acid (3 L×3). Two phases of the filtrate were separated,and the organic phase was back-extracted with 1N hydrochloric acid (25L×3). The water phases were combined, filtrated by filter cloth andfilter paper to remove insoluble solids. The filtrate was extracted withpetroleum ether (25 L) again. The water phase was added with ethylacetate (50 L), and the pH of the water phase was adjusted to 8-9 withsolid potassium carbonate under stirring. Two phases were separated, andthe water phase was extracted with ethyl acetate three times (30 L×3).The organic

30 phases were combined and concentrated under reduced pressure toprecipitate a large amount of white solids. The reaction mixture wascooled slightly, filtrated and dried to obtain the title product (45.8g, yield 50%).

¹H-NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 2H), 3.80 (s, 3H).

(4) Preparation of phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate

3-Methoxy-1,2,4-thiadiazol-5-amine (500 mg, 3.82 mmol) and phenylchloroformate (600 mg, 3.82 mmol) were dissolved in dichloromethane (20mL), then triethylamine (0.8 mL, 5.73 mmol) was added dropwise. Aftercompletion of the dropwise addition, the reaction solution was stirredfor 16 hours, added with water (30 mL) to dilute, and two phases wereseparated. The water phase was extracted with dichloromethane (20 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate,filtrated and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography with eluent(dichloromethane and methanol) to obtain the title product phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate (200 mg, yield 20.8%).

MS m/z (ESI): 252.2 [M+1]

¹H-NMR (400 MHz, CDCl₃) δ 12.33 (s, 1H), 7.46-7.42 (m, 2H),7.33-7.26 (m,3H), 4.01 (s, 3H).

Example 1. Preparation of(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(compound IV)

Preparation of tent-butyl(3aR,5s,6aS)-5-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(Ic)

4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 g, 0.98 mol),

N-BOC-bicyclooctanone (234 g, 0.98 mol) and N,N-dimethylformamide (2.3kg) were added to a reaction flask under a nitrogen atmosphere, andstirred to dissolve. The reaction solution was added with potassiumcarbonate (336 g, 2.44 mol), and warmed up to 100° C. under stirring for2 hours. After TLC showed that the reaction was completed, the reactionsolution was cooled to room temperature. The reaction solution was addedwith ice water (15 kg), and a large amount of khaki solids wereprecipitated. The reaction mixture was stirred at room temperature for 1hour and filtrated, and the filter cake was dissolved in dichloromethane(6 kg) and extracted. The organic phase was dried over anhydrous sodiumsulfate, filtrated and concentrated under reduced pressure to obtain acrude product. The crude product was dissolved in ethyl acetate (1.2 kg)under heating, and slowly added with petroleum ether (3.6 kg) at roomtemperature to precipitate a solid gradually. The reaction mixture wasstirred for 1 hour and filtrated, and the filter cake was dried underreduced pressure to obtain the title product (349 g, yield 70.0%).

Step 2

Preparation of tent-butyl(3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(IIa)

Tert-butyl

(3aR,5s,6aS)-5-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(315 g, 0.62 mol) and N,N-dimethylacetamide (1.5 kg) were added to areaction flask and stirred to dissolve. The reaction solution was addedwith potassium hydroxide (176 g, 3.15 mol), then added with water (300g) under stirring to precipitate a solid. The reaction mixture waswarmed up to 70° C. and stirred to react for 1 hour. After TLC showedthat the reaction was completed, the reaction solution was cooled toroom temperature. The reaction solution was added with dichloromethane(3.9 kg) and water (3.0 kg), and extracted. Two phases were separated,and the organic phase was dried over anhydrous sodium sulfate andfiltrated. The filtrate was concentrated under reduced pressure toobtain a light yellow solid, which was then added with a mixed solventof ethyl acetate/petroleum ether (1.0 kg, v/v=1/4) and pulped underheating at 50° C. for 0.5 hour. The reaction mixture was filtrated anddried under reduced pressure to obtain the title product (192 g, yield87.2%).

Step 3

Preparation ofN-methyl-N-((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(III)

Tert-butyl

(3aR,5s,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(187 g, 0.52 mol), anhydrous methanol and dichloromethane (0.8 kg,w/w=1.6) were added to a reaction flask and stirred to dissolve.Hydrochloric acid (0.55 kg, 15 mol) was added dropwise in an ice waterbath.

After completion of the addition, the reaction was stirred at roomtemperature for 10 hours. After TLC showed that the reaction wascompleted, the reaction solution was concentrated under reduced pressureto remove most of the organic solvent. The reaction solution was addedwith water (0.3 L) and extracted with dichloromethane (0.6 kg×3), andthe organic phase was removed. The water phase was adjusted to the pH9-10 by 30% sodium hydroxide solution, a large amount of solid wasprecipitated and filtrated. The solid was well pulped with purifiedwater (0.25 kg×2), filtrated and dried under reduced pressure to obtainthe title product (131 g, yield 97.3%).

Step 4

Preparation of(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(compound IV)N-methyl-N-((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(101 g, 0.39 mol), phenyl (3-methoxy-1,2,4-thiadiazole-5-yl)carbamate(106 g, 0.42 mol) and tetrahydrofuran (1.8 kg) were added to a reactionflask under a nitrogen atmosphere, and stirred well. Triethylamine (170g, 1.68 mol) was added. After completion of the addition, the reactionsolution was heated to reflux and stirred for 5 hours. After TLC showedthat the reaction was completed, the reaction solution was cooled toroom temperature and filtrated. The filter cake was washed withtetrahydrofuran (400 g) and anhydrous ethanol (200 g), and dried underreduced pressure to obtain the title product (157 g, yield 96.5%).

Purity determined by HPLC: 99%

MS m/z (ESI): 415.2 [M+1]

¹H-NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 11.59 (s, 1H), 8.10 (s, 1H),7.07 (m, 1H), 6.54-6.53 (m, 1H), 5.50-5.46 (m, 1H), 3.91-3.87 (s, 3H),3.73-3.60 (m, 2H), 3.37-3.33 (m, 2H), 3.19-3.16 (s, 3H), 2.89 (m, 2H),2.05-1.97 (m, 2H), 1.81-1.76 (m, 2H).

Example 2. Preparation of

(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamidedisulfate

(1) Preparation of the Crude Product

(3aR,5s,6aS)-N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide(140 g, 0.34 mol), anhydrous methanol (350 g) and dichloromethane (2.0kg) were added to a reaction flask and stirred. Sulfuric acid (34.8 g,0.36 mol) was slowly added dropwise at room temperature. The reactionsolution was clear and stirred for 30 minutes, and filtrated to removeinsoluble matters. The filtrate was concentrated under reduced pressureto obtain a solid, which was then added with anhydrous ethanol (700 mL)and stirred at room temperature for 4 hours. The reaction solution wasfiltrated and dried underreduced pressure to obtain crude(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamidedisulfate (160 g, yield 92.4%).

Purity determined by HPLC: 99%

(2) Purification of the Product

The crude(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamidedisulfate (145 g, 0.28 mol) and anhydrous methanol (11 kg) were added toa reaction flask. The reaction solution was heated to reflux until itwas clear, then filtrated while it was still hot, and concentrated underreduced pressure. The concentrated solution was cooled to roomtemperature, stirred to precipitate a crystal and filtrated. The filtercake was washed with anhydrous ethanol (200 g), and dried under reducedpressure to obtain purified(3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamidedisulfate (138 g, yield 95.2%).

Purity determined by HPLC: 99.4%

MS m/z (ESI): 415.2[M+1]

¹H-NMR (400 MHz, DMSO-d₆) δ 12.75 (s, 1H), 11.04 (s, 1H), 8.37 (s, 1H),7.42-7.41 (t, 1H), 6.89 (s, 1H), 5.19-5.15 (m, 1H), 3.89 (s, 3H),3.70-3.68(m, 2H), 3.40-3.38 (m, 2H), 3.29 (s, 3H), 2.95 (s, 2H),2.16-2.09 (m, 2H), 1.97-1.92 (m, 2H).

What is claimed is:
 1. A method for preparing a compound of formula (IV)or a pharmaceutically acceptable salt thereof, characterized in that themethod comprises a step of obtaining the compound of formula (IV) from acompound of formula (I′) by an one-step reaction or multi-step reaction,

wherein, R₂ is an amino protecting group; R₃ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl and an amino protecting group; theamino protecting group is selected from the group consisting ofalkoxycarbonyl amino protecting group, acyl amino protecting group,sulfonyl amino protecting group and alkyl amino protecting group; thealkoxycarbonyl amino protecting group is selected from the groupconsisting of benzyloxycarbonyl, tert-butoxycarbonyl,fluorenylmethoxycarbonyl, allyloxycarbonyl,trimethylsilylethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl; theacyl amino protecting group is selected from the group consisting ofphthalyl, trifluoroacetyl, pivaloyl, benzoyl, formyl and acetyl; thesulfonyl amino protecting group is selected from the group consisting ofp-toluenesulfonyl, o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl;and the alkyl amino protecting group is selected from the groupconsisting of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and benzyl.2. The method according to claim 1, characterized by obtaining thecompound of formula (IV) from a compound of formula (I′-1) by anone-step reaction or multi-step reaction,


3. A method for preparing a compound of formula (IV) or apharmaceutically acceptable salt thereof, characterized in that themethod comprises a step of obtaining the compound of formula (IV) from acompound of formula (Ic) by an one-step reaction or multi-step reaction,


4. A method for preparing a compound of formula (IV) or apharmaceutically acceptable salt thereof, characterized in that themethod comprises a step of reacting a compound of formula (III) with acompound (C) to obtain the compound of formula (IV),


5. The method according to claim 4, characterized in that the compoundof formula (III) is obtained by amino deprotection from a compound offormula (Ia),

wherein R₁ is hydrogen or an amino protecting group; R₂ is an aminoprotecting group; the amino protecting group is selected from the groupconsisting of alkoxycarbonyl amino protecting group, acyl aminoprotecting group, sulfonyl amino protecting group and alkyl aminoprotecting group; the alkoxycarbonyl amino protecting group is selectedfrom the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl,fluorenylmethoxycarbonyl, allyloxycarbonyl,trimethylsilylethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl; theacyl amino protecting group is selected from the group consisting ofphthalyl, trifluoroacetyl, pivaloyl, benzoyl, formyl and acetyl; thesulfonyl amino protecting group is selected from the group consisting ofp-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl;and the alkyl amino protecting group is selected from the groupconsisting of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and benzyl.6. The method according to claim 5, characterized in that the aminodeprotection reaction comprises the steps of,

step 1, removing an amino protecting group of the intermediate compoundof formula (Ia) to obtain an intermediate compound of formula (II); andstep 2, removing an amino protecting group of the intermediate compoundof formula (II) to obtain the compound of formula (III).
 7. The methodaccording to claim 6, characterized in that the deprotection reactioncomprises the steps of,


8. The method according claim 5, wherein R₁ is an alkoxycarbonyl aminoprotecting group, and the alkoxycarbonyl amino protecting group isselected from the group consisting of benzyloxycarbonyl,tert-butoxycarbonyl, fluorenylmethoxycarbonyl, and allyloxycarbonyl, andR2 is a sulfonyl amino protecting group, and the sulfonyl aminoprotecting group is selected from the group consisting ofp-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl.9. The method of claim 8, wherein R₁ is tert-butoxycarbonyl and R₂ isp-toluenesulfonyl.
 10. The method according to claim 7, characterized inthat the deprotection reaction comprises the following steps of,


11. The method according to claim 5, characterized in that the compoundof formula (III) is obtained by simultaneously removing the aminoprotecting groups of the compound of formula (Ia) by an one-stepreaction,


12. The method according to claim 11, characterized in that the compoundof formula (III) is obtained by simultaneously removing the aminoprotecting groups of a compound of formula (Ib) by an one-step reaction,


13. The method according to claim 11, wherein R₁ and R₂ are as definedin claim
 8. 14. The method according to claim 12, characterized in thatthe compound of formula (III) is obtained by removing the aminoprotecting groups of a compound of formula (Ic) by an one-step reaction,


15. A method for preparing a pharmaceutically acceptable salt of acompound of formula (IV), comprising the steps according to claim 1, anda step of reacting the compound of formula (IV) with an acid to obtainthe pharmaceutically acceptable salt thereof, wherein the acid isselected from the group consisting of an organic acid and an inorganicacid; the organic acid is selected from the group consisting of citricacid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid,maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acidand methanesulfonic acid; the inorganic acid is selected from the groupconsisting of hydrochloric acid, sulfuric acid and phosphoric acid.